1. Field of the Invention
This invention relates to the field of therapeutic compounds for the treatment of diseases of the skin and mucosal tissue. In particular the present invention relates to creams, ointments, eye and ear drops made from the herb Tribulus Terrestris that have a high content of spirostanol-type steroidal saponins and are useful in the treatment of conditions related to viral, fungal, yeast, parasitic and bacterial infections, particularly genital, skin (including acne) and eye and ear infections.
2. Description of the Related Art
Tribulus Terrestris, commonly known as xe2x80x9cPuncture Vinexe2x80x9d or Caltrop fruit, is an herb that has been used for centuries in Europe for hormone insufficiency in men and women. It has also been used in the treatment of liver, kidney and urinary tract disease. In recent years Tribulus Terrestris has been touted as a dietary supplement for improving athletic performance. It has been discovered that ingestion of Tribulus terrestris significantly elevates the level of several hormones: Testosterone; Luteinizing Hormone; Follicle Stimulating Hormone; and Estradiol. Clinical studies on Tribulus, conducted at the Chemical Pharmaceutical Institute in Sofia, Bulgaria, showed improved reproductive functions, including increased sperm production and Testosterone levels in men. Among women, Tribulus terrestris L. increased the concentration of hormones including Estradiol, with Testosterone being very slightly influenced, thereby improving reproductive function, libido and ovulation.
The active components of the Tribulus terrestris L. plant also have a stimulating effect on the immune, sexual and reproductive systems, leading to improved muscle building, stamina and endurance. Other positive changes observed in a number of cases were a reduction in cholesterol, enhanced mood and well-being. No adverse effects to the central nervous or cardiovascular systems were noted in any of the clinical studies.
The Tribulus plant is also of interest due to the increasing clinical importance of emerging pathogens as well as drug-resistant microorganisms, which lend additional urgency to identify novel, active compounds. Currently available drugs for the treatment of fungal infections include amphotericin B (a macrolide polyene), which interacts with fungal membrane sterols, flucytosine (a fluoropyrimidine), which interferes with fungal protein and DNA biosynthesis, and a variety of azoles (e.g. ketoconazole, itraconazole, and fluconazole) that inhibit fungal membrane-sterol biosynthesis (see e.g. Alexander, B. D. et al., Drugs, 1997, 54:657-678). Although amphotericin B has a broad range of activity and is viewed as the xe2x80x9cgold standardxe2x80x9d of antifungal therapy, its use is limited due to infusion-related reactions and nephrotoxicity (see Alexander, B. D. et al., Drugs, 1997, 54:657-678). Flucytosine usage is also limited due to the development of resistance and its narrow spectrum of activity. Further, the widespread use of azoles is causing the emergence of clinically-resistant strains of Candida spp. (see Alexander, B. D. et al., Drugs, 1997, 54:657-678). This problem is particularly important in treating vaginal infections due to bacteria, parasitis and fungi.
Other commonly used agents in treating vaginal infections include dimethylalkybenzalkonium choloride, nonylphenololyoxyethylene or nonoxynol-9. The use of these bacteriocidal agents in vaginally inserted suppositories, creams, foams or the like, however, is also not without problems inasmuch as these agents tend to diminish or destroy the healthy bacterial flora of the vagina, and cause a tendency to develop yeast infections (candidasis). Further, many of the prior art compositions have a narrow spectrum of action in that they cover only some of the microorganisms responsible for a particular condition.
In this respect, the Tribulus terrestris L. plant has been a promising alternative to existing xe2x80x9cchemicalxe2x80x9d anti-microbials. Tribulus terrestris L. contains saponins, which in plants, are formed from a sapogenin core linked with a sugar. The sapogenin, or glycoside, may be a steroid or a triterpene and the sugar moiety may be glucose, galactose, a pentose or a methyl pentose. Samples of Tribulus terrestris L. extract prepared according to the invention disclosed herein have been found to include tigogenine, diosgenin (a steroid sapogenin), desoxydiosgenin astragalin, kampferol (a flavanoid), dioscin (a furostanol that converts to diosgenin and glucose under hydrolysis), protodioscin (a furostanol), harmine (a bioflavanoide), linoleic acid, galactoolysaccharide, protogracillin and kampferol biofavanoide compounds. As with many secondary plant compounds, the concentration of saponins within a plant will vary depending upon the identity of the plant, the source of saponin within the plant (e.g. seed, fruit, leaves) and the conditions under which the plant is grown. The method of extraction will also affect the concentration of saponins. Generally, however, saponins are present in conventional extracts at about 15 to 25 percent by weight and average at about 20% by weight.
Saponins are also found in soybeans, alfalfa, and ginseng have been studied extensively for their effect of lowering cholesterol. For example, U.S. Pat. No. 4,242,502 issued to Malinow et al (1980) relates to the use of saponins to inhibit cholesterol absorption. According to this reference, modification of the oligosaccharide portion of the saponin by hydrolysis under mild acid conditions affects the saponins"" ability to affect cholesterol absorption. More particularly, when the sugar moiety of the saponin molecule is removed, i.e., the glycosidic linkage is cleaved, it was found that the cholesterol is no longer removed. Therefore, hyrolysis of saponin in the stomach or intestine is an important factor in considering the efficacy of saponin-containing therapeutic compound, for example, in the treatment of hypercholesterolemia. To this effect, U.S. Pat. No. 5,760,009 (Allen et al., 1998) discloses a crystalline monohydrate of a spirostanol glycoside that is not degraded in the digestive system and is useful for the control of hypercholesterolemia or atheroscerosis. Topical application of saponins also presents special consideration for therapeutic efficacy since not all saponins are topically bio-active.
The steriodal saponins found in the herb Tribulus terrestris are two types; furostanols and spirostanols. Furostanol steroidal saponins from Tribulus terrestris L. are not topically bio-active and must be first converted to spirostanols to become bioactive, for example, via enzyme hydrolysis. The instant invention discloses the use of Tribulus terresteris L. compositions having a high spirostanol saponin content useful in treating fungal, bacterial viral and parasitic infections and methods for making the same.
The present invention includes pharmacologic compositions derived from the herb Tribulus Terrestris L. that have a high content of spirostanol-type steroidal saponins and/or balance the ratio of furostanol to spirostanol-type saponins in the resulting composition. The compositions may be used topically, orally and on mucosal tissues and exhibit a strong anti-bacterial, anti-inflammation, anti-viral, and anti-herpes and hormone balancing effect. They are highly useful in treating vaginal infections, infertility, symptoms of menopause, skin disorders, bacterial infections and viral infections such as herpes simplex I and herpes simplex II, and in some cases may block cancer cells from growing. Treatment four times per day with tablets comprising about 250 mg of Tribulus terrestris extract was found to significantly alleviate symptoms associated with the presence of ovarian cysts and breast cysts. Tribulus terrestris L. compositions, as described herein, may be taken in tablet form to alleviate hormonal irregularities associated with conditions such as female infertility and the undesirable symptoms of menopause (e.g. xe2x80x9chot flashesxe2x80x9d).
The compositions disclosed herein, may be combined with ingredients known in the art to provide creams, ointments, oral tablets and eye and eardrops. For example, the present invention discloses a cream made from Tribulus Terrestris L. that has a very strong anti-bacterial, anti-inflammation, anti-virus, anti-herpes effect, represents a great improvement in the fields of dermatology and gynecology and satisfies a long felt need of dermatologists and gynecologists. Additionally, the compounds and methods disclosed herein are useful in treating cervical wounds, cervical erosion, diabetic wounds, Burger disease, phlebitis, rashes, skin burning, varicose veins and broken split skin.
The compositions disclosed herein, include preparations using methods comprising isolation, enzyme hydrolysis, and enrichment steps to optimize the spirostanol content of the resulting therapeutic composition. To prepare a preferred composition having optimal spirostanol content, a first extract is prepared by first carrying out, preferably, a low temperature water/alcohol extraction of the Tribulus Terrestris L. plant material. A number of factors are important in preparation of the Tribulus Terrestris L raw material and the extraction procedure. These include: time of harvesting the Tribulus terrestris L., part of the herb used, specific geographic area where the herb is gathered, the method of harvesting, and low temperature drying. Adherence to these factors guarantees high steroidal saponin, sapogenin and sterol content of the raw material used for making the extracts and resulting pharmacologic compositions.
For example, harvesting Tribulus terrestris L. from southern Bulgaria between approximately July first and August fifteenth ensures that the harvested Tribulus terrestris L. has a high saponin content. A sample of the crop to be harvested can be tested prior to harvesting according to the method disclosed in U.S. patent application Ser. No. 09/373,812 to further ensure that the Tribulus terrestris L. has optimal saponin content. Alternately, the crop to be harvested can be tested prior to harvesting according to the method disclosed in U.S. patent application Ser. No. 09/373,812, but using a general ratio of one part water to two and one half parts of dried raw plant material.
A water/alcohol extraction of the herb Tribulus Terrestris L may then be performed and the resulting extract concentrated with a vacuum evaporator. To prepare a highly bioactive extract of Tribulus terrestris L., spirostanol steroidal saponin, sterol and bio-flavanoides, are preferably isolated from a first Tribulus terrestris L. extract and are blended with a second Tribulus terrestris L. extract. More particularly, in a first step, the first extract is treated to hydrolyze furostanols contained in the extract to convert them into spirostanols. In a second step, the spirostanols in the first extract are isolated and added to a second prepared Tribulus terrestris L. extract. The resulting composition may be mixed with ingredients known in the art to form a cream, liquid, tablet or ointment and has been found to be very successful in suppository form for the treatment of bacterial, fungal, yeast, parasitic and bacterial infections.